Palladium(ii)-catalyzed γ-selective hydroarylation of alkenyl carbonyl compounds with arylboronic acids

Article abstract of DOI:10.1039/c8sc03081b

A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(ii) catalyst. This method tolerates a wide range of functionalized (hetero)arylboronic acids and a variety of substitution patterns on the alkene. Preliminary mechanistic studies suggest that transmetalation is rate-limiting.

Full text of DOI:10.1039/c8sc03081b

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Palladium(II)-Catalyzed γ-Selective Hydroarylation of Alkenyl
Carbonyl Compounds with Arylboronic Acids
Rei Matsuura,a Tanner C. Jankins,a David E. Hill,a Kin S. Yang,a Gary M. Gallego,b Shouliang Yang,b
Mingying He,b Fen Wang,b Rohan P. Marsters,a Indrawan McAlpine,b and Keary M. Engle*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalytic γ-selective syn-hydroarylation of alkenyl carbonyl that would complement existing methods.12
compounds using arylboronic acids has been developed using a
Scheme 1 Past and current work in C–C π-bond hydrocarbofunctionalization
substrate directivity approach with a palladium(II) catalyst. This
method tolerates wide range of functionalized
a
(hetero)arylboronic acids and a variety of substitution patterns on
the alkene. Preliminary mechanistic studies suggest that
transmetalation is rate-limiting.
Introduction
Transition-metal catalyzed 1,4-addition of arylboronic acids
to enones and related conjugated alkenes has emerged as a
reliable and robust method to introduce an aryl group at the β
position of
a
carbonyl compound or functional group
seminal study
equivalent. In 1997 Miyaura reported
a
describing Rh(I)-catalyzed β-selective hydroarylation of enones
using arylboronic acids (Scheme 1A).1 In 1998, Miyaura and
Hayashi reported an asymmetric version of this reaction.2
Since then, Hayashi has reported an array of β-selective
hydroarylation methods for many classes of alkenes in
conjugation with electron-withdrawing groups, including
esters,3 aldehydes,4 phosphonates,5 and sulfonyls.6 Hayashi
has also achieved δ-selective functionalization by utilizing
conjugation in α,β,γ,δ-unsaturated systems.7,8 However,
expanding this mode of reactivity to C–C π bonds remote from
and out of conjugation with a carbonyl group (e.g., the γ-
position) remains a challenge.9 Notably, Sigman and co-
workers have recently developed a powerful toolkit for remote
arylation reactions to access enantioenriched arylated
aldehydes from alkenyl alcohols using a redox-relay strategy
(Scheme 1B).10-11 The goal of the present study was to develop
a redox-neutral method for γ-selective hydroarylation of β,γ-
unsaturated carboxylic acid derivatives with arylboronic acids
using a substrate directivity approach, a mode of reactivity
Previously, our group13-18 and others19,20 have developed a
suite of chelation-controlled regioselective alkene
functionalization reactions using Daugulis’s 8-aminoquinoline
(AQ)21,22 directing group under palladium(II) catalysis. With 3-
butenoic-acid-derived substrates, the AQ directing group
forces an incoming nucleophile to attack the γ-position to form
the preferred five-membered palladacycle. The intermediate
then reacts with an electrophile to yield the hydro- or
difunctionalized product. In particular, the hydrocarbo-
functionalization of 3-butenoic acid derivatives using various
carbon nucleophiles has been reported (Scheme 1C).14, 19b Thus
far, nucleophile scope has been limited to 1,3-dicarbonyls, aryl
carbonyls, indoles, phenols, and related nucleophiles capable
of engaging in
a
Wacker-type anti-nucleopalladation
mechanism. The addition of general aryl nucleophiles in this
mode of catalysis remains an unmet challenge.20
Given the vast structural diversity of arylboronic acids and
their widespread commercial availability, we sought to achieve
analogous reactivity with this family of nucleophiles. We
envisioned that such a transformation would be useful given
that the γ-aryl carboxylic acid motif is found in multiple FDA-
approved drugs (e.g., Chlorambucil, Moexipril and Sitagliptin,
Fig. 1). The proposed approach would allow such molecules to
be synthesized in a modular fashion using synthetic logic that
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is appealing to medicinal chemists and would allow for facile under acidic conditions (Table 1, entry 1). Notably, during
synthesis of analogues.
preliminary screening we found that AQ out-performed
various alternative directing groups (see SI). Hence,
Fig. 1 FDA approved drug molecules containing γ-aryl acid motifs
subsequent optimization focused on AQ-containing alkene 1a
.
Aromatic solvents were found to be beneficial for the reaction
and could be used in combination with common polar solvents
(entry 2). Various acids and bases were then screened, leading
to the identification of NaF as a comparable alternative to
benzoic acid as a promoter (entries 2–6). Interestingly, other
fluoride bases did not have a similarly beneficial effect on the
reaction (entries 3, 4). Switching to 100% m-xylene as solvent
and lowering the concentration improved the mass balance
(entry 7).
Moreover, we envisioned that after substrate coordination,
the complex would undergo transmetalation with the
arylboronic acid, allowing for mechanistically distinct Heck-
type syn-selective delivery of the aryl group via 1,2-migratory
insertion. Afterwards, the intermediate would undergo
protodepalladation to yield the γ-arylated product (Scheme
1D).
Table 2 Boronic Acid Scopea
Results and Discussion
Table 1 Reaction Optimizationa
Acid/ base
PhCO2H
Solvent
Temp
1a
3a
1
2
MeCN (0.5 M)
120 °C
5%
27%
PhCO2H
KF
1:1 MeCN:m-xylene
120 °C
120 °C
120 °C
120 °C
120 °C
120 °C
3%
39%
51%
52%
6%
58%
22%
12%
11%
56%
40%
(0.5 M)
3b
4b
5b
6b
7
1:1 MeCN:m-xylene
(0.5 M)
CsF
1:1 MeCN:m-xylene
(0.5 M)
Na2CO3
NaF
1:1 MeCN:m-xylene
(0.5 M)
1:1 MeCN:m-xylene
(0.5 M)
NaF
m-xylene (0.1 M)
41%
8c
9c
NaF
m-xylene (0.1 M)
m-xylene (0.1 M)
80°C
80°C
37%
93%
55%
3%
PhCO2H
10d
11d,e
12d
NaF
NaF
NaF
PhCF3 (0.1 M)
PhCF3 (0.1 M)
toluene (0.1 M)
100 °C
100 °C
100 °C
0%
91%
63%
58%
39%
33%
a
Reaction conditions: 1a (0.1 mmol), 2a–2at (0.2 mmol), Pd(OAc)2 (10 mol %),
NaF (0.2 mmol), var. water in PhCF3 (0.1 mL), 100°C, 12 h. All percentages
correspond to isolated yields. b 80°C. c in 1:4 t-BuOH:PhCF3 (0.1 mL).
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Pd(OAc)2 (10 mol %), acid or
base (2 equiv), water (2.5 equiv), solvent, temperature, 5 h. b base (1 equiv). c 24
h. d 12 h. e 5% catalyst loading.
Further optimization of reaction temperature, time, and re-
screening of aromatic solvents yielded 91% of the desired
Based on our past work, we initiated our investigation product with NaF in 0.1 M benzotrifluoride (entries 8–10).
using AQ-masked 3-butenoic acid (1a) as the pilot alkene and Decreased catalyst loading lowered the yield and conversion
phenylboronic acid as the nucleophile. Gratifyingly, we were (entry 11). When the reaction was run in toluene, the yield
able to observe the desired hydroarylated product in 27% yield decreased substantially, illustrating the importance of the
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trifluoromethyl group on benzotrifluoride, perhaps for providing moderate to good yield (4f–4m). Other sterically
increased polarity (entry 12). Among several arylboron hindered alkenes, such as 1,1-disubstituted alkenes (4n) and
reaction partners that were attempted (see SI), only trisubstituted alkenes (4o) were reactive, albeit in low yields.
triphenylboroxine behaved similarly to phenylboronic acid (see Alcohols and protected amines on the substrate did not exhibit
SI). Boronic esters, on the other hand, did not lead to an inhibitory effect on the transformation (4e, 4m). When
formation of the desired product.
cyclic substrates were subjected to the reaction conditions, the
Having optimized the reaction, we proceeded to corresponding syn-hydroarylated products were exclusively
investigate the substrate scope and functional group formed (4p, 4q).
tolerance.25 As commercial boronic acids can contain varying
Scheme 2 Large-scale synthesis and deprotection.
amounts of water, for each example we screened 0, 1.5, or 2.5
equivalents of water to find the optimal amount (see SI).
Additionally, some boronic acids with polar functional groups
were found to be visibly insoluble in benzotrifluoride. In these
cases, a 1:4 mixture of t-BuOH and benzotrifluoride was
effective (see SI).
The reaction was found to tolerate an array of functional
groups on the aromatic ring of the boronic acid, including both
electron-donating and -withdrawing substituents, in both the
para and meta positions (Table 2, 3b–3v). Substituents on the
ortho position led to diminished yields, presumably due to
steric effects, yet in most cases yields were still moderate (3w–
z
). Our method also tolerated multi-substituted benzenes
To demonstrate the practicality and utility of this method,
two large-scale reactions were performed. When run on 1-
mmol scale or 7.1-mmol scale (1.5 g), the reaction gave
comparable yields to the small-scale reaction (Scheme 2A).
After hydroarylation, the AQ directing group was readily
cleaved to yield the free acid 6a in 94% yield (Scheme 2B).
Deprotection using Maulide’s milder ozonolysis conditions was
also viable, providing free acid 6b, albeit with lower yields
(Scheme 2B).26
(
3aa–3ad), protected catechols (3ae), napthalenes (3af),
various heterocycles including furans, protected pyrroles, and
indoles (3ag–3as), and alkenylboronic acids (3at, 3au). Though
pyridine-type heterocycles were not generally compatible, 6-
fluoro-3-pyridinylboronic acid was an exception and provided
16% yield (3ap).
Table 3 Alkene Scopea
Finally, a preliminary result indicates that this approach can
also be extended to alkyl coupling partners. Using slightly
modified conditions with methylboronic acid as the
nucleophile, we were able to observe formation of the desired
hydromethylation product in 18% yield. (Scheme 3). This is a
promising finding for future expansion of the reaction scope.
Scheme 3 Preliminary Result for Alkyl Boronic Acids
Mechanistic Studies
The broad scope of this transformation combined with the
critical role of water stoichiometry in catalytic efficiency
prompted us to perform several experiments to shed light on
key aspects of the reaction mechanism.
To identify the origin of the hydrogen atom in the
hydroarylated product, deuterium incorporation studies were
performed using deuterated reaction components. First, we
sought to probe potential H/D exchange reactivity of the
starting material and product. When starting material 1a was
subjected to reaction conditions using D2O in place of H2O,
H/D exchange was observed exclusively at the alkenyl position
(Scheme 4A).27 In contrast, H/D exchange with the
hydroarylated product 3a was not observed (Scheme 4B).
a Reaction conditions: 1b–1r (0.1 mmol), 2a (0.2 mmol), Pd(OAc)2 (10 mol %), NaF
(0.2 mmol), water (0.25 mmol) in PhCF3 (0.1 mL), 100°C, 12 h. All percentages
correspond to isolated yields. b 80°C. c in 1:4 t-BuOH: PhCF3 (0.1 mL).
We then probed the alkene scope for our method.
Substituents on the α-position were generally well tolerated
(Table 3, 4a–e). Internal alkenes were also compatible,
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When alkene 1a was then subjected to the standard reaction
We then performed reaction progress kinetic analysis
conditions with D2O, a mixture of bis-protio, mono-protio- (RPKA), which is a powerful method to determine the driving
mono-deutero, and bis-deutero products was obtained forces of a reaction from a minimal number of experiments.29
(Scheme 4C). The formation of bis-deutero product combined Same-excess experiments indicated that catalyst deactivation
with the observation that the product does not undergo H/D takes place during the reaction and that there is some degree
exchange establishes that water is a competent source of of product inhibition (see SI). The general form of the kinetic
protons/deuterons, consistent with
mechanism.
a
protodepalladation profiles (as can be seen in the representative cases of the H
versus D rate profiles, Scheme 4E), shows a sharp transition
between a faster initial rate and a slower rate at higher
conversions, which often indicates catalyst deactivation. A
plausible pathway for catalyst deactivation is arylboronic acid
homocoupling to generate catalytically inactive palladium(0).
Indeed, biphenyl was observed by GC-FID during kinetic
experiments. A series of different-excess experiments were
also performed to determine the orders of the various
reactants (summarized in Table 4, see SI for complete rate
Scheme 4 Deuterium-Labeling Studies
profiles). These experiments indicated positive order in [2a
]
and negative order in [1a] (see SI). Burés’s graphical method30
was used to compare rate profiles from experiments with
different catalyst amounts, and the results suggested that the
reaction is first-order in palladium (see SI).
Table 4 Dependence of initial rate on reagent concentration
0.005
0.004
0.003
0.002
0.001
0
Standard
Double [2a]o
Double [1]o
H2O
D2O
Standard conditions: [1a]0 = 0.1 M; [2a]0 = 0.2 M; [Pd(OAc)2] = 0.01 M; [NaF] = 0.2
M; [H2O] = 0.25 M; solvent = PhCF3; 100°C.
Collectively the above experimental observations are
consistent with the catalytic cycle depicted in Scheme 5. The
Pd(II) catalyst coordinates to the AQ directing group to
generate A. The observed H/D scrambling in 1a (Scheme 4A)
and the negative order in [1a] are consistent with the
formation of an off-cycle complex A’ via C(alkenyl)–H
activation. Intermediate A reacts via base-promoted, rate-
controlling transmetalation to form the aryl palladium complex
B which then undergoes syn-selective 1,2-migratory insertion
to form Pd(II) complex C. An irreversible protodepalladation
step involving water gives product-bound palladium complex
D, which dissociates to release the product and regenerate the
catalyst.
Interestingly, upon using PhB(OD)2 as the source of
deuterons, the reaction gave a dramatically different product
distribution, suggesting that while there is some H/D exchange
between the boronic acid and reaction medium, not all
protons/deuterons in the reaction system are in equilibrium
(Scheme 4D). Finally, a comparison of global rate profile
between reactions using H2O versus D2O gave kH/kD = 1.07
(Scheme 4E). If protodepalladation were the rate-determining
step, we would expect to see a larger KIE (even factoring in the
possibility of exchangeable protons/deuterons),28 suggesting
that protodepalladation is not the rate-determining step in the
present catalytic cycle.
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2
3
4
5
6
7
8
9
Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai, and N.
Miyaura, J. Am. Chem. Soc. 1998, 120, 5579.
Y. Takaya, T. Senda, H. Kurushima, M. Ogasawara, and T.
Hayashi, Tetrahedron: Asymmetry 1999, 10, 4047
T. Hayashi, N. Tokunaga, K. Okamoto, and R. Shintani, Chem.
Lett. 2005, 34, 1480.
T. Hayashi, T. Senda, Y. Takaya, and M. Ogasawara, J. Am.
Chem. Soc. 1999, 121, 11591.
T. Nishimura, Y. Takiguchi, and T. Hayashi, J. Am. Chem. Soc.
2012, 134, 9086.
T. Hayashi, S. Yamamoto, and N. Tokunaga, Angew. Chem.
Int. Ed. 2005, 44, 4224.
T. Nishimura, Y. Yasuhara, and T. Hayashi, Angew. Chem. Int.
Ed. 2006, 45, 5164.
For representative reports on Pd(II)-catalyzed β-selective
hydroarylation using arylboronic acids, see: a) T. Nishikata, Y.
Yamamoto, I. D. Gridnev and N. Miyaura, Organometallics,
2005, 24, 5025. (b) T. Nishikata, Y. Yamamoto and N.
Miyaura, Adv. Synth. Catal., 2007, 349, 1759. (c) T. Nishikata,
Y. Yamamoto and N. Miyaura, Angew. Chem. Int. Ed., 2003,
42, 2768. (d) X. Lu and S. Lin, J. Org. Chem., 2005, 70, 9651.
Scheme 5 Proposed Catalytic Cycle
[LnPdII]
3
1
ligand
substrate
dissociation
coordination
O
X
H
O
O
Ar
C–H activation
H
N
Pd
L
N
N
N
R
N
Pd
X
N
Pd
L
R
A
R
D
A'
protodepalladation
irreversible
transmetalation
rate-determining
ArB(OH)2, F–
H2O
O
N
O
N
N
Pd
L
N
Pd
migratory
insertion
R
Ar
Ar
R
C
B
Conclusions
In conclusion, we have developed
a regioselective
(e) B. Zhao and X. Lu, Org. Lett., 2006,
Hessen and A. Minnaard, Org. Lett., 2005,
8
, 5987. (f) F. Gini, B.
hydroarylation of 3-butenoic acid derivatives using readily
available arylboronic acids and a removable 8-aminoquinoline
directing group. Unlike previous methods that utilize anti-
nucleopalladation, this reaction proceeds via transmetalation
and syn-insertion. This reactivity paradigm dramatically
broadens the range of nucleophiles that can be employed and
allows for the preparation of diasteroisomeric products that
are distinct from previous methods. The reaction was found to
tolerate a wide range of substituents and functional groups on
the boronic acid and was completely regio- and
stereoselective. This method can also be run on larger scales
without significant decrease in yield, and facile removal of the
directing group was also demonstrated. Future investigation
will focus on expanding the scope to include more alkenyl and
alkyl boronic acids.
7, 5309. (g) K.
Kikushima, J. C. Holder, M. Gatti and B. M. Stoltz, J. Am.
Chem. Soc., 2011, 133, 6902. (h) A. L. Gottumukkala, K.
Matcha, M. Lutz, J. G. de Vries and A. J. Minnaard, Chem.
Eur. J., 2012, 18, 6907. (i) F. Wang, F. Chen, M. Qu, T. Li, Y.
Liu and M. Shi, Chem. Commun., 2013, 49, 3360. (i) Q. He, F.
Xie, G. Fu, M. Quan, C. Shen, G. Yang, I. D. Gridnev and W.
Zhang, Org. Lett., 2015, 17, 2250. (k) S. Chen, L. Wu, Q. Shao,
G. Yang, W. Zhang, Chem. Commun., 2018, 54, 2522.
10 E. W. Werner, T.-S. Mei, A. J. Burckle, and M. S. Sigman,
Science 2012, 338, 1455.
11 T.-S. Mei, E. W. Werner, A. J. Burckle, and M. S. Sigman, J.
Am. Chem. Soc. 2013, 135, 6830.
12 For representative recent reports on alternative catalytic
approaches to alkene hydroarylation, see: (a) S. M.
Podhaisky, Y. Iwai, A. Cook-Sneathen, and M. S. Sigman,
Tetrahedron 2011, 67, 4435. (b) Y. Schramm, M. Takeuchi, K.
Semba, Y. Nakao, and J. F. Hartwig, J. Am. Chem. Soc. 2015,
137, 12215. (c) K. Semba, K. Ariyama, H. Zheng, R.
Kameyama, S. Sakaki, and Y. Nakao, Angew. Chem. Int. Ed.
2016, 55, 6275. (d) S. A. Green, J. L. M. Matos, A. Yagi, and R.
A. Shenvi, J. Am. Chem. Soc. 2016, 138, 12779. (e) S. D. Friis,
M. T. Pirnot, L. N. Dupuis, and S. L. Buchwald, Angew. Chem.
Int. Ed. 2017, 56, 7242. (f) L.-J. Xiao, L. Cheng, W.-M. Feng,
M.-L. Li, J.-H. Xie, and Q.-L. Zhou, Angew. Chem. Int. Ed.
2018, 57, 461.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
13 J. A. Gurak, K. S. Yang, Z. Liu, and K. M. Engle, J. Am. Chem.
Soc. 2016, 138, 5805.
14 K. S. Yang, J. A. Gurak, Z. Liu, and K. M. Engle, J. Am. Chem.
Soc. 2016, 138, 14705.
15 Z. Liu, T. Zeng, K. S. Yang, and K. M. Engle, J. Am. Chem. Soc.
2016, 138, 15122.
16 J. A. Gurak, V. T. Tran, M. M. Sroda, and K. M. Engle,
Tetrahedron 2017, 73, 3636.
17 Z. Liu, Y. Wang, Z. Wang, T. Zeng, P. Liu, and K. M. Engle, J.
Am. Chem. Soc. 2017, 139, 11261.
18 Z. Liu, H.-Q. Ni, T. Zeng, and K. M. Engle, J. Am. Chem. Soc.
2018, 140, 3223.
19 (a) E. P. A. Talbot, T. d. A. Fernandes, J. M. McKenna, and F.
D. Toste, J. Am. Chem. Soc. 2014, 136, 4101. (b) H. Wang, Z.
Bai, T. Jiao, Z. Deng, H. Tong, G. He, Q. Peng, and G. Chen, J.
Am. Chem. Soc. 2018, 140, 3542.
This work was financially supported by The Scripps
Research Institute (TSRI), Pfizer, Inc., Bristol-Myers Squibb
(Unrestricted Grant) and the National Institutes of Health
(1R35GM125052). We thank Prof. Arnold L. Rheingold and Dr.
Milan Gembicky (UCSD) for X-ray crystallographic analysis, Dr.
Dee-Hua Huang and Dr. Laura Pasternack for assistance with
NMR spectroscopy, Dr. Jason S. Chen and Brittany Sanchez for
help with compound purification, Prof. Donna G. Blackmond
with guidance with RPKA, and Prof. Will R. Gutekunst (Georgia
Tech) and Prof. Nuno Maulide (University of Vienna) for
helpful discussion.
20 Two related studies were disclosed while this manuscript
was in revision. For a report using nickel(0) catalysis, see: (a)
H. Lu, L.-J. Xiao, D. Zhao, and Q.-L. Zhou, Chem. Sci. 2018, 9,
Notes and references
1
M. Sakai, H. Hayashi, and N. Miyaura, Organometallics, 1997,
16, 4229.
6839. For a reductive Heck approach, see: (b) C. Wang, G.
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Xiao, T. Guo, Y. Ding, X. Wu, and T.-P. Loh, J. Am. Chem. Soc.
2018,140, 9332.
21 For a representative review, see: O. Daugulis, H.-Q. Do, and
D. Shabashov, Acc. Chem. Res., 2009, 42, 1074.
22 For representative reports on Pd(II)-catalyzed directed γ-
arylation of carbonyl compounds via C(sp3)–H activation, see:
(a) B. V. S. Reddy, L. R. Reddy, and E. J. Corey, Org. Lett.,
2006, 8, 3391. (b) G. He, S.-Y. Zhang, W. A. Nack, R. Pearson,
J. Rabb-Lynch, G. Chen, Org. Lett., 2014, 16, 6488. (c) A. Dey,
S. Pimparkar, A. Deb, S. Guin, and D. Maiti, Adv. Synth. Catal.
2017, 359, 1301.
23 The 2017 WHO Essential Medicines List can be found at
http://www.who.int/medicines/publications/essentialmedici
nes/en/
24 The annual sales for Januvia® (Sitagliptin) can be found at
http://investors.merck.com/news/press-release-
details/2017/Merck-Announces-Fourth-Quarter-and-Full-
Year-2016-Financial-Results
25 For low-yielding examples, the reactions typically only
reached low conversion. In these cases, roughly 90% of the
material could be accounted for as starting alkene (1) or (3);
the remaining material (approximately 10%) was consumed
via alkene reduction.
26 M. Berger, R. Chauhan, C. A. B. Rodrigues, and N. Maulide,
Chem. Eur. J. 2016, 22, 16805.
27 For an example of similar reactivity involving a six-membered
palladacycle, see: M. Liu, P. Yang, M. K. Karunananda, Y.
Wang, P. Liu, and K. M. Engle, J. Am. Chem. Soc. 2018, 140,
5805.
28 J. Derosa, A. L. Cantu, M. N. Boulous, M. L. O’Duill, J. L.
Turnbull, Z. Liu, D. M. De La Torre, and K. M. Engle, J. Am.
Chem. Soc. 2017, 139, 5183.
29 D. G. Blackmond, Angew. Chem. Int. Ed. 2005, 44, 4302.
30 J. Burés, Angew. Chem. Int. Ed., 2016, 55, 2028.
6 | J. Name., 2012, 00, 1-3
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Chemical Science
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DOI: 10.1039/C8SC03081B
TOC image
O
R2
cat. Pd(II)
ArB(OH)2
R2 H
O
R3
Ar
N
AQ
H
N
R1
R1 R3
>60 examples
(AQ)
operationally convenient
removable directing group
A catalytic γꢀselective synꢀhydroarylation of alkenyl carbonyl compounds using arylboronic acids has been
developed using a substrate directivity approach with a palladium(II) catalyst.